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Keywords:

  • evolution;
  • jawless vertebrates;
  • pattern recognition receptors;
  • variable lymphocyte receptors

Abstract

  1. Top of page
  2. Abstract
  3. ADAPTIVE IMMUNE RESPONSES IN JAWLESS VERTEBRATES
  4. ANTIGEN RECEPTORS IN JAWLESS VERTEBRATES
  5. ASSEMBLY OF VLR GENES
  6. STRUCTURE OF ANTIGEN-VLR COMPLEXES
  7. T AND B CELL-LIKE LYMPHOCYTE LINEAGES IN JAWLESS VERTEBRATES
  8. CONVERGENT EVOLUTION OF ADAPTIVE IMMUNITY IN VERTEBRATES
  9. REPERTOIRE OF PATTERN RECOGNITION RECEPTORS IN DEUTEROSTOMES
  10. TOLL-LIKE RECEPTORS AND RIG-I LIKE RECEPTORS AND THEIR SIGNAL TRANSDUCTION IN JAWED VERTEBRATES
  11. TOLL-LIKE RECEPTOR AND RIG-I LIKE RECEPTOR PATHWAYS: INSIGHTS FROM THE LAMPREY GENOME
  12. CROSSTALK BETWEEN INNATE AND ADAPTIVE IMMUNITY IN JAWLESS VERTEBRATES
  13. CONCLUSIONS AND PERSPECTIVE
  14. ACKNOWLEDGMENTS
  15. DISCLOSURE
  16. REFERENCES

Because jawless vertebrates are the most primitive vertebrates, they have been studied to gain understanding of the evolutionary processes that gave rise to the innate and adaptive immune systems in vertebrates. Jawless vertebrates have developed lymphocyte-like cells that morphologically resemble the T and B cells of jawed vertebrates, but they express variable lymphocyte receptors (VLRs) instead of the T and B cell receptors that specifically recognize antigens in jawed vertebrates. These VLRs act as antigen receptors, diversity being generated in their antigen-binding sites by assembly of highly diverse leucine-rich repeat modules. Therefore, jawless vertebrates have developed adaptive immune systems based on the VLRs. Although pattern recognition receptors, including Toll-like receptors (TLRs) and Rig-like receptors (RLRs), and their adaptor genes are conserved in jawless vertebrates, some transcription factor and inflammatory cytokine genes in the TLR and RLR pathways are not present. However, like jawed vertebrates, the initiation of adaptive immune responses in jawless vertebrates appears to require prior activation of the innate immune system. These observations imply that the innate immune systems of jawless vertebrates have a unique molecular basis that is distinct from that of jawed vertebrates. Altogether, although the molecular details of the innate and adaptive immune systems differ between jawless and jawed vertebrates, jawless vertebrates have developed versions of these immune systems that are similar to those of jawed vertebrates.

List of Abbreviations:
AID

activation-induced cytosine deaminase

APC

antigen presenting cell

BCR

B cell receptor

CARD

caspase recruitment domain

CCR9

chemokine (C-C motif) receptor 9

CD

cluster of differentiation

CDA

cytidine deaminase

CP

connecting peptide

c-Rel

c-reticuloendotheliosis oncogene

CXCR2

chemokine (C-X-C motif) receptor 2

DC

dendritic cell

ds

double-stranded

GPI

glycoprotein I

gVLR

germ-line VLR

HEL

hen egg lysozyme

HVI

highly variable insert

IFN

interferon

IL

interleukin

IPS-1

IFN-β-promoter stimulator 1

IRF

interferon regulatory transcription factor

LGP2

laboratory of genetics and physiology-2

LLC

lymphocyte-like cell

LRR

leucine-rich repeat

LRRCT

C-terminal LRR

LRRNT

N-terminal LRR

MDA5

melanoma differentiation-associated gene 5

MHC

major histocompatibility complex

MyD88

myeloid differentiation protein-88

NFκB

nuclear factor of κ light polypeptide gene enhancer in B cells

NLR

nucleotide-binding oligomerization domain-containing protein-like receptor

NOD

nucleotide-binding oligomerization domain containing

PAMP

pathogen-associated molecular pattern

poly I:C

polyriboinosinic-polyribocytidylic acid

PRR

pattern recognition receptor

RAG

recombination-activating gene

RIG-I:

retinoic acid-inducible protein I

RLR

Rig-I like receptor

SP

signal peptide

ss

single-stranded

TCR

T cell receptor

TICAM-1

Toll-IL-1 receptor domain-containing adaptor molecule 1

TIR

toll-interleukin 1 receptor

TLR

toll-like receptor

TNF

tumor necrosis factor

VLR

variable lymphocyte receptor

Vertebrate immune systems have innate and adaptive immunity components. In these immune systems, different types of receptors play important roles in pathogen recognition.

Innate immunity provides the first line of defense against pathogens. In the innate immune system, PRRs, such as the TLRs, NLRs and RLRs, recognize PAMPs [1]. Recognition of PAMPs rapidly induces antimicrobial responses in infected cells and activates innate immune cells, including macrophages and DCs, that act as APCs[2].

In contrast, antigen-specific responses and immunological memory characterize the adaptive immunity system. In this immune system, TCRs and BCRs act as antigen-specific receptors on T and B cells, respectively. An assembly of variable (V) and joining (J), or V, diversity (D) and J gene fragments generate variability in the antigen-binding regions of these receptors [3]. RAGs mediate rearrangement of the antigen receptor genes. The antigen receptors allow the organisms to have an immune repertoire that is able to specifically recognize virtually any antigen. Whereas BCRs and their soluble form, antibodies, directly recognize antigens, TCRs recognize processed antigen peptide and MHC molecule complexes on infected cells and APCs [4].

Activated APCs produce inflammatory cytokines and activate CD8+ killer and CD4+ helper T cells through MHC-TCR interactions and costimulatory signals [5]. Thereafter, activated helper T cells control production of antigen-specific antibodies from B cells [6]. Therefore, activation of innate immunity through PRRs is required for initiation of adaptive immunity mediated by T and B cells.

Vertebrates are classified as jawed and jawless [7]. Because jawless vertebrates are the most primitive vertebrates, they have been studied to gain understanding of the evolutionary processes that gave rise to the innate and adaptive immune systems in vertebrates ([8][10]). In this review, we will summarize the innate and adaptive immune systems of jawless vertebrates and the convergent evolution of these systems in vertebrates.

ADAPTIVE IMMUNE RESPONSES IN JAWLESS VERTEBRATES

  1. Top of page
  2. Abstract
  3. ADAPTIVE IMMUNE RESPONSES IN JAWLESS VERTEBRATES
  4. ANTIGEN RECEPTORS IN JAWLESS VERTEBRATES
  5. ASSEMBLY OF VLR GENES
  6. STRUCTURE OF ANTIGEN-VLR COMPLEXES
  7. T AND B CELL-LIKE LYMPHOCYTE LINEAGES IN JAWLESS VERTEBRATES
  8. CONVERGENT EVOLUTION OF ADAPTIVE IMMUNITY IN VERTEBRATES
  9. REPERTOIRE OF PATTERN RECOGNITION RECEPTORS IN DEUTEROSTOMES
  10. TOLL-LIKE RECEPTORS AND RIG-I LIKE RECEPTORS AND THEIR SIGNAL TRANSDUCTION IN JAWED VERTEBRATES
  11. TOLL-LIKE RECEPTOR AND RIG-I LIKE RECEPTOR PATHWAYS: INSIGHTS FROM THE LAMPREY GENOME
  12. CROSSTALK BETWEEN INNATE AND ADAPTIVE IMMUNITY IN JAWLESS VERTEBRATES
  13. CONCLUSIONS AND PERSPECTIVE
  14. ACKNOWLEDGMENTS
  15. DISCLOSURE
  16. REFERENCES

Jawless vertebrates, including lampreys and hagfish, and jawed vertebrates are sister groups (Fig. 1). Molecular phylogenetic and paleontological studies indicate that these two groups of vertebrates diverged approximately 500 million years ago [7], [11]. Studies of jawless vertebrates have identified LLCs, which are morphologically similar to the T and B cells of jawed vertebrates [12]. Moreover, like jawed vertebrates, jawless vertebrates are capable of producing antigen-specific agglutinins and of forming immunological memory regarding rejection of skin allografts [13], [14]. These findings indicate that jawless vertebrates possess adaptive immunity that is similar to that of jawed vertebrates. However, recent transcriptome analyses of LLCs have failed to identify important molecules that are central to the adaptive immunity of jawed vertebrates, such as the TCRs, BCRs, MHCs and RAGs (Fig. 1) [15], [16]. Hence, jawless vertebrates have a unique adaptive immune system that is not based on those molecules.

image

Figure 1. Pathogen recognition receptors in deuterostomes. Whereas BCRs and TCRs are conserved in jawed vertebrates and VLRs in jawless vertebrates, pattern recognition receptors, including TLRs, RLRs and NLRs, are highly conserved in all deuterostomes.

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ANTIGEN RECEPTORS IN JAWLESS VERTEBRATES

  1. Top of page
  2. Abstract
  3. ADAPTIVE IMMUNE RESPONSES IN JAWLESS VERTEBRATES
  4. ANTIGEN RECEPTORS IN JAWLESS VERTEBRATES
  5. ASSEMBLY OF VLR GENES
  6. STRUCTURE OF ANTIGEN-VLR COMPLEXES
  7. T AND B CELL-LIKE LYMPHOCYTE LINEAGES IN JAWLESS VERTEBRATES
  8. CONVERGENT EVOLUTION OF ADAPTIVE IMMUNITY IN VERTEBRATES
  9. REPERTOIRE OF PATTERN RECOGNITION RECEPTORS IN DEUTEROSTOMES
  10. TOLL-LIKE RECEPTORS AND RIG-I LIKE RECEPTORS AND THEIR SIGNAL TRANSDUCTION IN JAWED VERTEBRATES
  11. TOLL-LIKE RECEPTOR AND RIG-I LIKE RECEPTOR PATHWAYS: INSIGHTS FROM THE LAMPREY GENOME
  12. CROSSTALK BETWEEN INNATE AND ADAPTIVE IMMUNITY IN JAWLESS VERTEBRATES
  13. CONCLUSIONS AND PERSPECTIVE
  14. ACKNOWLEDGMENTS
  15. DISCLOSURE
  16. REFERENCES

Novel rearranging antigen receptors, the VLRs, have been identified as the candidate molecules that mediate adaptive immune responses of jawless vertebrates [17]. In some mitogen- and antigen-stimulated sea lampreys, many VLR transcripts containing variable numbers of diverse LRRs can be identified in activated LLCs. VLRs encode a SP, an LRRNT, multiple LRRs, a CP, a LRRCT and an invariant stalk region (2a). Based on consensus motifs and length, the LRRs are classified according to the most N-terminal LRR1 (18 residues), the most C-terminal LRRVe (24 residues) and the LRRV (24 residues) that is located between the LRR1 and the LRRVe. In each VLR transcript, the sequence of each LRR module is distinct and the number of LRRV modules variable.

image

Figure 2. Structure and assembly of VLRs. (a) Domain structure of mature VLRs. (b) Comparison of gVLR genes. The organization of gVLR genes differs in each gene and species. (c) Assembly of VLR genes. Multiple LRRNT-, LRR1-, LRRV-, LRRVe-, CP- and LRRCT-encoding modules are located proximal to the gVLR genes. During development of LLCs, these modules are incorporated into the gVLR genes. If the first VLR gene is successfully rearranged, then gene rearrangement is suppressed at the other gVLR locus. In contrast, if the first gVLR gene fails to generate an nonfunctional gene, then gene rearrangement occurs in the other gVLR locus.

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Before somatic rearrangement, the gVLR gene is incapable of encoding a functional protein. Two VLR genes, designated VLRA and VLRB, have been identified in hagfish and lampreys [18], [19]. VLRB was first described in sea lampreys. In hagfish, the VLRA and VLRB loci are located far apart on the same chromosome [20]. Recently, a third VLR gene, termed VLRC, was identified in lampreys [21]. It is still unknown whether hagfish possess a VLRC gene. The organization of these gVLR genes differs depending on the gene and species (2b).

The possible combinations of VLRA and VLRB are estimated to generate a potential repertoire that is almost equivalent to the TCRs and BCRs of jawed vertebrates, (> 1014) [22]. This observation suggests that VLRs are the antigen receptors of jawless vertebrates. Consistent with this, lampreys immunized with human erythrocytes or anthrax spores of Bacillus anthracis produce antigen-specific soluble VLRB molecules that act as antibodies [22], [23]. These observations indicate that, despite their lack of structural similarity to the antigen receptors of jawed vertebrates, VLRs function as antigen receptors in jawless vertebrates.

ASSEMBLY OF VLR GENES

  1. Top of page
  2. Abstract
  3. ADAPTIVE IMMUNE RESPONSES IN JAWLESS VERTEBRATES
  4. ANTIGEN RECEPTORS IN JAWLESS VERTEBRATES
  5. ASSEMBLY OF VLR GENES
  6. STRUCTURE OF ANTIGEN-VLR COMPLEXES
  7. T AND B CELL-LIKE LYMPHOCYTE LINEAGES IN JAWLESS VERTEBRATES
  8. CONVERGENT EVOLUTION OF ADAPTIVE IMMUNITY IN VERTEBRATES
  9. REPERTOIRE OF PATTERN RECOGNITION RECEPTORS IN DEUTEROSTOMES
  10. TOLL-LIKE RECEPTORS AND RIG-I LIKE RECEPTORS AND THEIR SIGNAL TRANSDUCTION IN JAWED VERTEBRATES
  11. TOLL-LIKE RECEPTOR AND RIG-I LIKE RECEPTOR PATHWAYS: INSIGHTS FROM THE LAMPREY GENOME
  12. CROSSTALK BETWEEN INNATE AND ADAPTIVE IMMUNITY IN JAWLESS VERTEBRATES
  13. CONCLUSIONS AND PERSPECTIVE
  14. ACKNOWLEDGMENTS
  15. DISCLOSURE
  16. REFERENCES

During development of LLCs, LRR modules are inserted into the gVLR gene by a gene conversion-like mechanism (2c) [19], [24]. Multiple LRRNT-, LRR1-, LRRV-, LRRVe-, CP- and LRRCT-encoding modules are located proximally to the gVLR gene. A homologous sequence is used to prime the insertion of those modules during VLR assembly. The sequences located at the ends of the most newly copied LRR module determine the next LRR module. In this way, LRR modules are unidirectionally inserted into the gVLR gene. Although, monoallelic assembly of the VLRA and VLRB genes occurs in the majority of cases, diallelic assembly has been observed in a few cases [25]. In such instances, one mature VLR gene encodes a functional VLR structure, while the other does not. The unsuccessful mature VLR gene contains an in-frame stop codon. These observations indicate that an inhibitory feedback mechanism regulates VLR assembly.

The molecular mechanism of VLR assembly is still unknown. However, two CDAs, CDA1 and CDA2, have been identified as candidate molecules that may mediate gene conversion [19]. Generation of antibody diversity by gene conversion in birds, rabbits and cattle requires AID, which belongs to the apolipoprotein B mRNA editing enzyme, catalytic polypeptide family of molecules [26]. Phylogenetic analysis and secondary structure prediction suggest that AID and CDA1 are more closely related to each other than are AID and CDA2. Over-expression of the CDA1 molecule in yeast confers a mutagenic phenotype and increases the rate of intragenic recombination. Previous reports have revealed that CDA1 and CDA2 are expressed in VLRA+ and VLRB+ LLCs, respectively [27]. Thus, the jawless vertebrate CDA1 and CDA2 molecules may control gene conversion-like processes in VLRA+ and VLRB+ LLCs, respectively.

STRUCTURE OF ANTIGEN-VLR COMPLEXES

  1. Top of page
  2. Abstract
  3. ADAPTIVE IMMUNE RESPONSES IN JAWLESS VERTEBRATES
  4. ANTIGEN RECEPTORS IN JAWLESS VERTEBRATES
  5. ASSEMBLY OF VLR GENES
  6. STRUCTURE OF ANTIGEN-VLR COMPLEXES
  7. T AND B CELL-LIKE LYMPHOCYTE LINEAGES IN JAWLESS VERTEBRATES
  8. CONVERGENT EVOLUTION OF ADAPTIVE IMMUNITY IN VERTEBRATES
  9. REPERTOIRE OF PATTERN RECOGNITION RECEPTORS IN DEUTEROSTOMES
  10. TOLL-LIKE RECEPTORS AND RIG-I LIKE RECEPTORS AND THEIR SIGNAL TRANSDUCTION IN JAWED VERTEBRATES
  11. TOLL-LIKE RECEPTOR AND RIG-I LIKE RECEPTOR PATHWAYS: INSIGHTS FROM THE LAMPREY GENOME
  12. CROSSTALK BETWEEN INNATE AND ADAPTIVE IMMUNITY IN JAWLESS VERTEBRATES
  13. CONCLUSIONS AND PERSPECTIVE
  14. ACKNOWLEDGMENTS
  15. DISCLOSURE
  16. REFERENCES

Jawless vertebrates possess both soluble and membrane-bound forms of VLRB [17], [28]. Soluble VLRB antibodies are organized into pentamers or tetramers of dimers, similarly to immunoglobulin M of jawed vertebrates. The cysteine residues that are located in the 3′-invariant stalk region are required for VLRB antibodies to form oligomers. The membrane-bound form of VLRB is a glycosyl-phosphatidylinositol anchored protein that undergoes cleavage in the stalk region. Interestingly, VLRB-transfected human cell lines, such as HEK293T cells, produce oligomeric VLRB antibodies. Therefore, cell lines transfected with a VLRB-enriched cDNA library derived from immunized lamprey LLCs can establish antigen-specific VLRB monoclonal antibodies. These VLRB antibodies retain antigen binding ability even after storage for > 12 months at 4°C, 1 month at room temperature, or 36 hrs at 56°C. Additionally, although these VLRB antibodies cannot be eluted from an antigen-affinity column with high salt concentrations or under extremely acidic conditions (pH < 1.5), they can be eluted under highly basic conditions (pH > 11). This suggests that VLRB antibodies may be useful natural single-chain alternatives to immunoglobulin-based antibodies for biotechnology applications.

Crystallographic analysis of VLRA and VLRB has shown that they adopt a horseshoe-shaped structure in lampreys and hagfish (Fig. 3) [29], [30]. The crystal structure of VLRC is not yet available; however, three-dimensional modeling predicts that the overall structure of VLRC is similar to that of VLRA and VLRB. Parallel beta sheets that contain most of the variable residues form the concave surface. Recently, crystallographic analyses of VLRA and VLRB binding to HEL were reported [31], [32]. In these VLR-HEL complexes, HEL binds with VLRA and VLRB molecules via both LRR modules and protrusions in the LRRCT domain. A stretch of amino acid residues known as the HVI, which is highly variable in length, amino acid composition and secondary structure, forms these protrusions (Fig. 3) [29]. Unlike VLRA and VLRB, VLRC lacks HVI in the LRRCT domain. This structural feature might impose additional restrictions on the nature of antigens recognized by VLRC.

image

Figure 3. Structural conformation of VLR molecules. Crystal structures of HEL bound to lamprey VLRA (PDB ID 3 M18) and VLRB (PDB ID 3G3A) molecules and the predicted conformation of lamprey VLRC (accession number AB507273). The arrowheads in the LRRCT domain mark the HVI, which displays marked variations in length, amino acid composition and secondary structure.

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T AND B CELL-LIKE LYMPHOCYTE LINEAGES IN JAWLESS VERTEBRATES

  1. Top of page
  2. Abstract
  3. ADAPTIVE IMMUNE RESPONSES IN JAWLESS VERTEBRATES
  4. ANTIGEN RECEPTORS IN JAWLESS VERTEBRATES
  5. ASSEMBLY OF VLR GENES
  6. STRUCTURE OF ANTIGEN-VLR COMPLEXES
  7. T AND B CELL-LIKE LYMPHOCYTE LINEAGES IN JAWLESS VERTEBRATES
  8. CONVERGENT EVOLUTION OF ADAPTIVE IMMUNITY IN VERTEBRATES
  9. REPERTOIRE OF PATTERN RECOGNITION RECEPTORS IN DEUTEROSTOMES
  10. TOLL-LIKE RECEPTORS AND RIG-I LIKE RECEPTORS AND THEIR SIGNAL TRANSDUCTION IN JAWED VERTEBRATES
  11. TOLL-LIKE RECEPTOR AND RIG-I LIKE RECEPTOR PATHWAYS: INSIGHTS FROM THE LAMPREY GENOME
  12. CROSSTALK BETWEEN INNATE AND ADAPTIVE IMMUNITY IN JAWLESS VERTEBRATES
  13. CONCLUSIONS AND PERSPECTIVE
  14. ACKNOWLEDGMENTS
  15. DISCLOSURE
  16. REFERENCES

VLR genes are assembled in distinct populations of LLCs. VLRB+ LLCs respond to antigens by undergoing lymphoblastoid transformation, proliferating and differentiating into plasmacytes that secrete multimeric antigen-specific VLRB antibodies [23]. In contrast, VLRA+ LLCs respond to T cell mitogens by upregulating their expression of IL-17 in a manner that is similar to that of T helper 17 cells in jawed vertebrates, but not by secreting VLRA molecules [27]. The gene expression profiles of VLRA+ and VLRB+ LLCs are similar to those of mammalian T and B cells, respectively. For example, VLRA+ LLCs express genes associated with T cell differentiation and development (e.g., GATA binding protein 2/3, c-Rel, aryl hydrocarbon receptor, B cell leukemia/lymphoma 11B and CD45). VLRB+ LLCs express both spleen tyrosine kinase and B cell adaptor protein, which function in BCR-mediated signal transduction. In mammals, helper CD4+ T cells are required for antibody production from activated B cells. Interestingly, VLRA+ LLCs express IL-17 and the receptor for IL-8, whereas VLRB+ LLCs express IL-8 and the receptor for IL-17. These cytokines and their receptors may play a role in crosstalk between VLRA+ and VLRB+ LLCs.

Rearrangement of the VLRC gene occurs in VLRA/VLRB LLCs [21]. Phylogenetic analysis of VLR genes indicates that the VLRC sequence is more closely related to the VLRA than the VLRB sequence. This suggests that, like VLRA+ LLCs, VLRC+ LLCs may be classified as T cell-like LLCs. These observations indicate that jawless vertebrates have developed an adaptive immune system based on VLR+ LLC subsets that are similar to the T and B cells of jawed vertebrates.

Recently, thymus-like epithelial structures termed “thymoids” were identified in the filaments and neighboring secondary lamellae of lamprey larvae [33]. The forkhead box N1 gene, which is a molecular marker of the thymopoietic microenvironment in jawed vertebrates, is expressed in thymoids. Interestingly, unsuccessfully rearranged VLRA sequences are found only in thymoids, whereas the sequences obtained from blood are all successful. These findings seem to indicate that the thymoids of jawless vertebrates are the functional analogue of the thymi of jawed vertebrates.

CONVERGENT EVOLUTION OF ADAPTIVE IMMUNITY IN VERTEBRATES

  1. Top of page
  2. Abstract
  3. ADAPTIVE IMMUNE RESPONSES IN JAWLESS VERTEBRATES
  4. ANTIGEN RECEPTORS IN JAWLESS VERTEBRATES
  5. ASSEMBLY OF VLR GENES
  6. STRUCTURE OF ANTIGEN-VLR COMPLEXES
  7. T AND B CELL-LIKE LYMPHOCYTE LINEAGES IN JAWLESS VERTEBRATES
  8. CONVERGENT EVOLUTION OF ADAPTIVE IMMUNITY IN VERTEBRATES
  9. REPERTOIRE OF PATTERN RECOGNITION RECEPTORS IN DEUTEROSTOMES
  10. TOLL-LIKE RECEPTORS AND RIG-I LIKE RECEPTORS AND THEIR SIGNAL TRANSDUCTION IN JAWED VERTEBRATES
  11. TOLL-LIKE RECEPTOR AND RIG-I LIKE RECEPTOR PATHWAYS: INSIGHTS FROM THE LAMPREY GENOME
  12. CROSSTALK BETWEEN INNATE AND ADAPTIVE IMMUNITY IN JAWLESS VERTEBRATES
  13. CONCLUSIONS AND PERSPECTIVE
  14. ACKNOWLEDGMENTS
  15. DISCLOSURE
  16. REFERENCES

The evolutionary precursors of TCR and BCR genes, known as the TCR-like and agnathan-paired receptor resembling antigen receptor genes [34], [35], were found by transcriptome analysis of LLCs in jawless vertebrates. These receptors are composed of one or two immunoglobulin domains that have weak similarity to those of TCRs and BCRs. It has been proposed that an ancestor of the VLR gene arose from a GPIbα-like gene that is conserved in all vertebrates [19]. The genomic structure and characteristic insert in the LRRCT domain of the GPIbα gene is similar to those found in VLR genes. These findings indicate that ancestral VLR and TCR/BCR genes were present in a common ancestor of jawless and jawed vertebrates (Fig. 4). Moreover, the gene expression profiles of each LLC subset indicate that the ancestral VLRA/VLRC/T and VLRB/B cell lineages also developed in a common ancestor. After the jawed and jawless vertebrate lineages diverged, the ancestral TCR/BCR and VLR genes became antigen receptors in the jawed and jawless vertebrates, respectively. Following development of these rearranging antigen receptors, further diversification at the genetic and cellular levels occurred independently in each vertebrate lineage. Jawed and jawless vertebrates ultimately developed similar adaptive immune systems.

image

Figure 4. Convergent evolution of the adaptive immune systems in vertebrates. A common ancestor of jawed and jawless vertebrates may have possessed ancestral BCR/TCR and VLR genes. Additionally, there were ancestral VLRA/C/T and VLRB/B cell lineages in the common vertebrate ancestor. After the jawed and jawless vertebrate lineages diverged, the ancestral TCR/BCR and VLR genes became antigen receptors in jawed and jawless vertebrates, respectively. Following development of rearranging antigen receptors, further diversification at the genetic and cellular levels occurred independently in each vertebrate lineage.

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REPERTOIRE OF PATTERN RECOGNITION RECEPTORS IN DEUTEROSTOMES

  1. Top of page
  2. Abstract
  3. ADAPTIVE IMMUNE RESPONSES IN JAWLESS VERTEBRATES
  4. ANTIGEN RECEPTORS IN JAWLESS VERTEBRATES
  5. ASSEMBLY OF VLR GENES
  6. STRUCTURE OF ANTIGEN-VLR COMPLEXES
  7. T AND B CELL-LIKE LYMPHOCYTE LINEAGES IN JAWLESS VERTEBRATES
  8. CONVERGENT EVOLUTION OF ADAPTIVE IMMUNITY IN VERTEBRATES
  9. REPERTOIRE OF PATTERN RECOGNITION RECEPTORS IN DEUTEROSTOMES
  10. TOLL-LIKE RECEPTORS AND RIG-I LIKE RECEPTORS AND THEIR SIGNAL TRANSDUCTION IN JAWED VERTEBRATES
  11. TOLL-LIKE RECEPTOR AND RIG-I LIKE RECEPTOR PATHWAYS: INSIGHTS FROM THE LAMPREY GENOME
  12. CROSSTALK BETWEEN INNATE AND ADAPTIVE IMMUNITY IN JAWLESS VERTEBRATES
  13. CONCLUSIONS AND PERSPECTIVE
  14. ACKNOWLEDGMENTS
  15. DISCLOSURE
  16. REFERENCES

The TLR repertoire is unique to each animal (Table 1). TLR1/TLR2 and TLR6/TLR2 complexes recognize triacyl and diacyl lipoproteins, respectively [36]. Orphan TLR14 and TLR15 molecules are members of the TLR2 subfamily, which also includes TLR1, TLR2 and TLR6 [37], [38]. TLR3 binds viral dsRNA in endolysosomes, whereas TLR22 is conserved in aquatic animals and recognizes dsRNA on cell surfaces ([29][42]). TLR4 recognizes bacterial lipopolysaccharide together with myeloid differentiation factor 2 on cell surfaces [43]. TLR5 recognizes flagellin in flagellated bacteria. TLR7 and TLR8 recognize ssRNAs from RNA viruses [44]. TLR9 detects unmethylated DNA containing CpG motifs, which are derived from bacteria and viruses [45]. Likewise, TLR 21 is conserved in birds and aquatic animals and recognizes CpG motifs [46]. TLR11 recognizes profilin-like molecules derived from Toxoplasma gondii. The ligands for TLR10, TLR12 and TLR13 are still unknown [47].

Table 1. TLRs, RLRs and their adaptor genes in deuterostomes.
 HumansMiceChickensFrogsZebrafishPuffer fishLampreysAscidiansAmphioxusSea urchins
  1. +, exists; –, does not exist; psd, pseudogene.

TLR1++++++   
TLR2++++++   
TLR3+++++++   
TLR4+++++   
TLR5+++++++   
TLR6++psd   
TLR7+++++++   
TLR8++++++   
TLR9+++++336> 200
TLR10+psd   
TLR11/12+++   
TLR13++   
TLR14++++   
TLR15+   
TLR21+++++   
TLR22/23++++   
TLR24+   
MyD88++++++++++
TICAM-1++++++++
RIG-I++++++
MDA5+++++++
IPS-1++++++++
TBK1++++++++++
IKKε++++++++++
IRF3+++++
IRF7++++++
NF-κB++++++++++
IL-12p40++++++
IL-6++++++
TNFα+++++++
Type I IFN++++++

The RLR family recognizes PAMPs in the cytoplasm. The RLR family that detects RNA viruses consists of RIG-I, MDA5 and LGP2 [1], [48]. RIG-I and MDA5 are composed of two N-terminal CARDs, a central DEAD box helicase/ATPase domain and a C-terminal regulatory domain. LGP2 has a similar structure, but lacks a CARD domain.

Interestingly, the PRR families, such as TLRs, have greatly expanded in certain invertebrates such as the amphioxus and sea urchins (Table 1) [49], [50]. In contrast, only a few TLR genes have been found in the ascidian Ciona intestinalis genome [51]. Surprisingly, one of the Ciona TLRs recognizes both dsRNA and flagellin [52]. These examples suggest that complex innate mechanisms are required to defend against pathogens in the absence of an adaptive immune system (Fig. 1).

TOLL-LIKE RECEPTORS AND RIG-I LIKE RECEPTORS AND THEIR SIGNAL TRANSDUCTION IN JAWED VERTEBRATES

  1. Top of page
  2. Abstract
  3. ADAPTIVE IMMUNE RESPONSES IN JAWLESS VERTEBRATES
  4. ANTIGEN RECEPTORS IN JAWLESS VERTEBRATES
  5. ASSEMBLY OF VLR GENES
  6. STRUCTURE OF ANTIGEN-VLR COMPLEXES
  7. T AND B CELL-LIKE LYMPHOCYTE LINEAGES IN JAWLESS VERTEBRATES
  8. CONVERGENT EVOLUTION OF ADAPTIVE IMMUNITY IN VERTEBRATES
  9. REPERTOIRE OF PATTERN RECOGNITION RECEPTORS IN DEUTEROSTOMES
  10. TOLL-LIKE RECEPTORS AND RIG-I LIKE RECEPTORS AND THEIR SIGNAL TRANSDUCTION IN JAWED VERTEBRATES
  11. TOLL-LIKE RECEPTOR AND RIG-I LIKE RECEPTOR PATHWAYS: INSIGHTS FROM THE LAMPREY GENOME
  12. CROSSTALK BETWEEN INNATE AND ADAPTIVE IMMUNITY IN JAWLESS VERTEBRATES
  13. CONCLUSIONS AND PERSPECTIVE
  14. ACKNOWLEDGMENTS
  15. DISCLOSURE
  16. REFERENCES

The TLRs bind the two adaptor proteins, MyD88 and TICAM-1 (5a) [53]. MyD88 is an adaptor protein for all the TLRs except TLR3 and TLR22, whereas TICAM-1 is an adaptor protein for TLR3, TLR4 and TLR22. The MyD88 pathway primarily activates NF-κB and induces production of inflammatory cytokines such as IL-12p40, IL-6 and TNFα. The TICAM-1 pathway activates NF-κB and IRF3. Activation of IRF3 induces production of type I IFN. Binding of either TLR7 or TLR9 to their respective ligands induces IRF7-mediated production of type I IFN in plasmacytoid DCs through the MyD88 pathway [54]. RLRs bind IPS-1, which is located on the outer membrane of the mitochondria [55]. IPS-1 primarily activates IRF3 and enhances production of type I interferon; however, it also activates the NF-κB pathway.

image

Figure 5. Signal transduction of TLR and RLR pathways. (a) TLR and RLR pathways in mammalians. (b) Hypothetical TLR and RLR pathways in lampreys. MyD88 is an adaptor protein for all the TLRs except TLR3 and TLR22, whereas TICAM-1 is an adaptor protein for TLR3, TLR4 and TLR22. The MyD88 pathway primarily activates NF-κB and induces production of inflammatory cytokines such as IL-12p40, IL-6 and TNFα. The TICAM-1 pathway activates NF-κB and IRF3 and induces production of inflammatory cytokines including type I IFN. Stimulation of TLR7 and TLR9 with their ligands is unique in inducing IRF7-mediated production of type I IFN in plasmacytoid dendritic cells via the MyD88 pathway. IPS-1 on mitochondria is an adaptor protein for RIG-I and MDA5. The IPS-1 pathway primarily induces IRF3-mediated production of type I IFN, but it also activates NF-κB.

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TOLL-LIKE RECEPTOR AND RIG-I LIKE RECEPTOR PATHWAYS: INSIGHTS FROM THE LAMPREY GENOME

  1. Top of page
  2. Abstract
  3. ADAPTIVE IMMUNE RESPONSES IN JAWLESS VERTEBRATES
  4. ANTIGEN RECEPTORS IN JAWLESS VERTEBRATES
  5. ASSEMBLY OF VLR GENES
  6. STRUCTURE OF ANTIGEN-VLR COMPLEXES
  7. T AND B CELL-LIKE LYMPHOCYTE LINEAGES IN JAWLESS VERTEBRATES
  8. CONVERGENT EVOLUTION OF ADAPTIVE IMMUNITY IN VERTEBRATES
  9. REPERTOIRE OF PATTERN RECOGNITION RECEPTORS IN DEUTEROSTOMES
  10. TOLL-LIKE RECEPTORS AND RIG-I LIKE RECEPTORS AND THEIR SIGNAL TRANSDUCTION IN JAWED VERTEBRATES
  11. TOLL-LIKE RECEPTOR AND RIG-I LIKE RECEPTOR PATHWAYS: INSIGHTS FROM THE LAMPREY GENOME
  12. CROSSTALK BETWEEN INNATE AND ADAPTIVE IMMUNITY IN JAWLESS VERTEBRATES
  13. CONCLUSIONS AND PERSPECTIVE
  14. ACKNOWLEDGMENTS
  15. DISCLOSURE
  16. REFERENCES

TLRs, RLRs and adaptor genes of lampreys are summarized in Table 1. The lamprey genome sequence contains at least 16 TLR genes [56]. Single loci of the TLR3, TLR5 and TLR22 genes are found in the genome, whereas multiple loci of the TLR14, TLR21, TLR7/8 and TLR24 genes have arisen from lamprey and/or jawless vertebrate-specific gene duplication events.

Four TLR24 genes, which are novel TLR2 subfamily genes, form a unique cluster independent of the mammalian TLR1, TLR2 and TLR6 genes (Fig. 6). TLR14d forms a cluster together with the jawed vertebrate TLR14 genes, while TLR14a, TLR14b and TLR14c form a cluster independent of the other TLR14 genes. These findings suggest that lampreys have two types of TLR14 genes. Two TLR7- and TLR8-related genes, TLR7/8a and TLR7/8b, have been mapped to the root of the jawed vertebrate TLR7 and TLR8 cluster. These observations indicate that the TLR7/8 genes are the ancestral genes of the vertebrate TLR7 and TLR8 genes. Three TLR adaptor genes, MyD88, TICAM-1a and TICAM-1b, are contained in the lamprey genome sequence. Comparison with the jawed vertebrate TICAM-1 gene indicates that TICAM-1a and b are the ortholog and ancestral genes of the jawed vertebrate TICAM-1, respectively. RIG-I, LGP2, and their adaptor IPS-1 are conserved in the lamprey genome, while MDA5 is not found. Interestingly, although NF-κB and its activating genes, such as TBK1 and IKKε, are highly conserved among vertebrates, IRF3, IRF7, type I IFN and inflammatory cytokine genes, such as IL-12p40, IL-6 and TNFα, have not been found in the lamprey genome.

image

Figure 6. Phylogenetic tree of the vertebrate TLRs. Bootstrap values (> 69) are indicated as filled (85∼100) or open (70∼84) circles. Lamprey TLRs are represented by red characters. Abbreviations: Dr, zebrafish (Danio rerio); Gg, chicken (Gallus gallus); Hs, human (Homo sapiens); Lj, Japanese lamprey (Lethentron japonicum); Mm, mouse (Mus musculus); Pm, sea lamprey (Petromyzon marinus); Tr, puffer fish (Takifugu rubripes); Xt, frog (Xenopus tropicalis).

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These observations imply that the TLR and RLR pathways are incomplete in jawless vertebrates. Because IL-12 and type I IFN play important roles in direct or indirect activation and differentiation of T cell subsets in jawed vertebrates, their absence in jawless vertebrates implies that the molecular basis of the innate immune system in jawless vertebrates is distinct from that of jawed vertebrates (5b) [57], [58].

CROSSTALK BETWEEN INNATE AND ADAPTIVE IMMUNITY IN JAWLESS VERTEBRATES

  1. Top of page
  2. Abstract
  3. ADAPTIVE IMMUNE RESPONSES IN JAWLESS VERTEBRATES
  4. ANTIGEN RECEPTORS IN JAWLESS VERTEBRATES
  5. ASSEMBLY OF VLR GENES
  6. STRUCTURE OF ANTIGEN-VLR COMPLEXES
  7. T AND B CELL-LIKE LYMPHOCYTE LINEAGES IN JAWLESS VERTEBRATES
  8. CONVERGENT EVOLUTION OF ADAPTIVE IMMUNITY IN VERTEBRATES
  9. REPERTOIRE OF PATTERN RECOGNITION RECEPTORS IN DEUTEROSTOMES
  10. TOLL-LIKE RECEPTORS AND RIG-I LIKE RECEPTORS AND THEIR SIGNAL TRANSDUCTION IN JAWED VERTEBRATES
  11. TOLL-LIKE RECEPTOR AND RIG-I LIKE RECEPTOR PATHWAYS: INSIGHTS FROM THE LAMPREY GENOME
  12. CROSSTALK BETWEEN INNATE AND ADAPTIVE IMMUNITY IN JAWLESS VERTEBRATES
  13. CONCLUSIONS AND PERSPECTIVE
  14. ACKNOWLEDGMENTS
  15. DISCLOSURE
  16. REFERENCES

In mammals, the TLR and RLR pathways play a critical role in activation of T and B adaptive immune cells [53]. For example, dsRNA such as poly I:C acts as an adjuvant, enhancing adaptive immune responses through the TLR3/TICAM-1 and MDA5/IPS-1 pathways. In TICAM-1 and IPS-1 deficient mice, both antigen-specific antibody production and CD8+ T cell expansion are decreased after poly I:C stimulation [59]. Previous studies have also shown that antigen-specific antibody production in jawless vertebrates is effectively induced against microbes containing PAMPs, which act as adjuvants, in comparison with purified protein antigens [14]. Hence, as in jawed vertebrates, initiation of adaptive immune responses in jawless vertebrates appears to require prior activation of the innate immune system.

Recently, myeloid cells that resemble DCs in mammals have been identified in teleost fish [60], [61]. Activation of these DC-like cells by stimulation with TLR ligands induces expression of IL-12p40 and maturation marker CD83 similarly to mammalian DCs. Moreover, DC-like cells are not only highly phagocytic of foreign antigens such as bacteria but also enhance proliferation of antigen-specific T cells.

Previous studies in jawless vertebrates have shown that polymorphonuclear myeloid cells phagocytose mammalian erythrocytes [62]. Additionally, the TLR3 and TLR5 genes, which are expressed in mammalian DCs and teleost DC-like cells, are expressed in VLRA/VLRB cells [27]. These observations indicate that VLRA/VLRB myeloid cells, which phagocytose foreign antigens, may function as accessory cells that activate the VLR-based adaptive immune system.

CONCLUSIONS AND PERSPECTIVE

  1. Top of page
  2. Abstract
  3. ADAPTIVE IMMUNE RESPONSES IN JAWLESS VERTEBRATES
  4. ANTIGEN RECEPTORS IN JAWLESS VERTEBRATES
  5. ASSEMBLY OF VLR GENES
  6. STRUCTURE OF ANTIGEN-VLR COMPLEXES
  7. T AND B CELL-LIKE LYMPHOCYTE LINEAGES IN JAWLESS VERTEBRATES
  8. CONVERGENT EVOLUTION OF ADAPTIVE IMMUNITY IN VERTEBRATES
  9. REPERTOIRE OF PATTERN RECOGNITION RECEPTORS IN DEUTEROSTOMES
  10. TOLL-LIKE RECEPTORS AND RIG-I LIKE RECEPTORS AND THEIR SIGNAL TRANSDUCTION IN JAWED VERTEBRATES
  11. TOLL-LIKE RECEPTOR AND RIG-I LIKE RECEPTOR PATHWAYS: INSIGHTS FROM THE LAMPREY GENOME
  12. CROSSTALK BETWEEN INNATE AND ADAPTIVE IMMUNITY IN JAWLESS VERTEBRATES
  13. CONCLUSIONS AND PERSPECTIVE
  14. ACKNOWLEDGMENTS
  15. DISCLOSURE
  16. REFERENCES

Although the molecular details of the innate and adaptive immune systems differ between jawless and jawed vertebrates, both immune systems are similar in jawless vertebrates and jawed vertebrates. The functions of VLRA+ and VLRC+ LLCs and the mechanisms of self-tolerance in thymoids are still unknown. Additionally, the molecular and cellular basis for crosstalk between the innate and adaptive immune systems in jawless vertebrates is also unclear. Future immunological studies in jawless vertebrates will uncover the convergent evolution and molecular details of innate and adaptive immune systems.

REFERENCES

  1. Top of page
  2. Abstract
  3. ADAPTIVE IMMUNE RESPONSES IN JAWLESS VERTEBRATES
  4. ANTIGEN RECEPTORS IN JAWLESS VERTEBRATES
  5. ASSEMBLY OF VLR GENES
  6. STRUCTURE OF ANTIGEN-VLR COMPLEXES
  7. T AND B CELL-LIKE LYMPHOCYTE LINEAGES IN JAWLESS VERTEBRATES
  8. CONVERGENT EVOLUTION OF ADAPTIVE IMMUNITY IN VERTEBRATES
  9. REPERTOIRE OF PATTERN RECOGNITION RECEPTORS IN DEUTEROSTOMES
  10. TOLL-LIKE RECEPTORS AND RIG-I LIKE RECEPTORS AND THEIR SIGNAL TRANSDUCTION IN JAWED VERTEBRATES
  11. TOLL-LIKE RECEPTOR AND RIG-I LIKE RECEPTOR PATHWAYS: INSIGHTS FROM THE LAMPREY GENOME
  12. CROSSTALK BETWEEN INNATE AND ADAPTIVE IMMUNITY IN JAWLESS VERTEBRATES
  13. CONCLUSIONS AND PERSPECTIVE
  14. ACKNOWLEDGMENTS
  15. DISCLOSURE
  16. REFERENCES
  • 1
    Takeuchi O., Akira S. (2010) Pattern recognition rkeceptors and inflammation. Cell 140: 80520.
  • 2
    Mellman I., Steinman R.M. (2001) Dendritic cells: specialized and regulated antigen processing machines. Cell 106: 2558.
  • 3
    Schatz D.G., Ji Y. (2011) Recombination centres and the orchestration of V(D)J recombination. Nat Rev Immunol 11: 25163.
  • 4
    Rudolph M.G., Stanfield R.L., Wilson I.A. (2006) How TCRs bind MHCs, peptides, and coreceptors. Annu Rev Immunol 24: 41966.
  • 5
    Castellino F., Germain R.N. (2006) Cooperation between CD4+ and CD8+ T cells: when, where, and how. Annu Rev Immunol 24: 51940.
  • 6
    Mauri C., Bosma A. (2012) Immune regulatory function of B cells. Annu Rev Immunol 30: 22141.
  • 7
    Janvier P., Arsenault M. (2002) Palaeobiology: calcification of early vertebrate cartilage. Nature 417: 609.
  • 8
    Boehm T., McCurley N., Sutoh Y., Schorpp M., Kasahara M., Cooper M.D. (2012) VLR-based adaptive immunity. Annu Rev Immunol 30: 20320.
  • 9
    Flajnik M.F., Kasahara M. (2010) Origin and evolution of the adaptive immune system: genetic events and selective pressures. Nat Rev Genet 11: 4759.
  • 10
    Good R.A., Finstand J. (1964) Phylogenetic development of transplantation immunity. Ann N Y Acad Sci 120: 1520.
  • 11
    Kuraku S., Meyer A., Kuratani S. (2009) Timing of genome duplications relative to the origin of the vertebrates: did cyclostomes diverge before or after? Mol Biol Evol 26: 4759.
  • 12
    Finstad J., Papermaster B., Good R.A. (1964) Evolution of the immune response. II. Morphologic studies on the origin of the thymus and organized lymphoid tissue. Lab Invest 13: 490512.
  • 13
    Perey D., Finstad J., Pollara B., Good R.A. (1968) Evolution of the immune response. VI. First and second set skin homograft rejections in primitive fishes. Lab Invest 19: 5917.
  • 14
    Finstad J., Good R.A. (1964) The evolution of the immune response. 3. Immunologic responses in the lamprey. J Exp Med 120: 115168.
  • 15
    Uinuk-Ool T., Mayer W., Sato A., Dongak R., Cooper M.D., Klein J. (2002) Lamprey lymphocyte-like cells express homologs of genes involved in immunologically relevant activities of mammalian lymphocytes. Proc Natl Acad Sci U S A 99: 1435661.
  • 16
    Suzuki T., Shin-I T., Kohara Y., Kasahara M. (2004) Transcriptome analysis of hagfish leukocytes: a framework for understanding the immune system of jawless fishes. Dev Comp Immunol 28: 9931003.
  • 17
    Pancer Z., Amemiya C.T., Ehrhardt G., Ceitlin J., Gartland G., Cooper M.D. (2004) Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey. Nature 430: 17480.
  • 18
    Pancer Z., Saha N.R., Kasamatsu J., Suzuki T., Amemiya C.T., Kasahara M, Cooper M.D. (2005) Variable lymphocyte receptors in hagfish. Proc Natl Acad Sci U S A 102: 92249.
  • 19
    Rogozin I., Iyer L., Liang L., Glazko G., Liston V., Pavlov Y., Aravind L., Pancer Z. (2007) Evolution and diversification of lamprey antigen receptors: evidence for involvement of an AID-APOBEC family cytosine deaminase. Nat Immunol 8: 64756.
  • 20
    Kasamatsu J., Suzuki T., Ishijima J., Matsuda Y., Kasahara M. (2007) Two variable lymphocyte receptor genes of the inshore hagfish are located far apart on the same chromosome. Immunogenetics 59: 32931.
  • 21
    Kasamatsu J., Sutoh Y., Fugo K., Otsuka N., Iwabuchi K., Kasahara M. (2010) Identification of a third variable lymphocyte receptor in the lamprey. Proc Natl Acad Sci U S A 107: 143048.
  • 22
    Alder M., Rogozin I., Iyer L., Glazko G., Cooper M.D., Pancer Z. (2005) Diversity and function of adaptive immune receptors in a jawless vertebrate. Science 310: 19703.
  • 23
    Alder M., Herrin B., Sadlonova A., Stockard C., Grizzle W., Gartland L., Gartland G., Boydston J., Turnbough C.J., Cooper M.D. (2008) Antibody responses of variable lymphocyte receptors in the lamprey. Nat Immunol 9: 31927.
  • 24
    Nagawa F., Kishishita N., Shimizu K., Hirose S., Miyoshi M., Nezu J., Nishimura T., Nishizumi H., Takahashi Y., Hashimoto S., Takeuchi M., Miyajima A., Takemori T., Otsuka A., Sakano H. (2007) Antigen-receptor genes of the agnathan lamprey are assembled by a process involving copy choice. Nat Immunol 8: 20613.
  • 25
    Kishishita N., Matsuno T., Takahashi Y., Takaba H., Nishizumi H., Nagawa F. (2010) Regulation of antigen-receptor gene assembly in hagfish. EMBO Rep 11: 12632.
  • 26
    Flajnik M.F. (2002) Comparative analyses of immunoglobulin genes: surprises and portents. Nat Rev Immunol 2: 68898.
  • 27
    Guo P., Hirano M., Herrin B., Li J., Yu C., Sadlonova A., Cooper M.D. (2009) Dual nature of the adaptive immune system in lampreys. Nature 459: 796801.
  • 28
    Herrin B., Alder M., Roux K., Sina C., Ehrhardt G., Boydston J., Turnbough C.J., Cooper M.D. (2008) Structure and specificity of lamprey monoclonal antibodies. Proc Natl Acad Sci U S A 105: 20405.
  • 29
    Han B., Herrin B., Cooper M.D., Wilson I. (2008) Antigen recognition by variable lymphocyte receptors. Science 321: 18347.
  • 30
    Kim H., Oh S., Lim K., Kasamatsu J., Heo J., Park B., Lee H., Yoo O., Kasahara M., Lee J. (2007) Structural diversity of the hagfish variable lymphocyte receptors. J Biol Chem 282: 672632.
  • 31
    Velikovsky C., Deng L., Tasumi S., Iyer L., Kerzic M., Aravind L., Pancer Z., Mariuzza R. (2009) Structure of a lamprey variable lymphocyte receptor in complex with a protein antigen. Nat Struct Mol Biol 16: 72530.
  • 32
    Deng L., Velikovsky C.A., Xu G., Iyer L.M., Tasumi S., Kerzic M.C., Flajnik M.F., Aravind L., Pancer Z., Mariuzza R.A. (2010) A structural basis for antigen recognition by the T cell-like lymphocytes of sea lamprey. Proc Natl Acad Sci U S A 107: 1340813.
  • 33
    Bajoghli B., Guo P., Aghaallaei N., Hirano M., Strohmeier C., McCurley N., Bockman D.E., Schorpp M., Cooper M.D., Boehm T. (2011) A thymus candidate in lampreys. Nature 470: 904.
  • 34
    Pancer Z., Mayer W., Klein J., Cooper M.D. (2004) Prototypic T cell receptor and CD4-like coreceptor are expressed by lymphocytes in the agnathan sea lamprey. Proc Natl Acad Sci U S A 101: 132738.
  • 35
    Suzuki T., Shin-I T., Fujiyama A., Kohara Y., Kasahara M. (2005) Hagfish leukocytes express a paired receptor family with a variable domain resembling those of antigen receptors. J Immunol 174: 288591.
  • 36
    Kirschning C.J, Schumann R.R. (2002) TLR2: cellular sensor for microbial and endogenous molecular patterns. Curr Top Microbiol Immunol 270: 12144.
  • 37
    Ishii A., Matsuo A., Sawa H., Tsujita T., Shida K., Matsumoto M., Seya T. (2007) Lamprey TLRs with properties distinct from those of the variable lymphocyte receptors. J Immunol 178: 397406.
  • 38
    Roach J., Glusman G., Rowen L., Kaur A., Purcell M., Smith K., Hood L., Aderem A. (2005) The evolution of vertebrate Toll-like receptors. Proc Natl Acad Sci U S A 102: 957782.
  • 39
    Alexopoulou L., Holt A., Medzhitov R., Flavell R. (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413: 7328.
  • 40
    Matsuo A., Oshiumi H., Tsujita T., Mitani H., Kasai H., Yoshimizu M., Matsumoto M., Seya T. (2008) Teleost TLR22 recognizes RNA duplex to induce IFN and protect cells from birnaviruses. J Immunol 181: 347485.
  • 41
    Ishii A., Kawasaki M., Matsumoto M., Tochinai S., Seya T. (2007) Phylogenetic and expression analysis of amphibian Xenopus Toll-like receptors. Immunogenetics 59: 28193.
  • 42
    Oshiumi H., Tsujita T., Shida K., Matsumoto M., Ikeo K., Seya T. (2003) Prediction of the prototype of the human Toll-like receptor gene family from the pufferfish, Fugu rubripes, genome. Immunogenetics 54: 791800.
  • 43
    Poltorak A., He X., Smirnova I., Liu M.Y., Van Huffel C., Du X., Birdwell D., Alejos E., Silva M., Galanos C., Freudenberg M., Ricciardi-Castagnoli P., Layton B., Beutler B. (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282: 20858.
  • 44
    Jurk M., Heil F., Vollmer J., Schetter C., Krieg A.M., Wagner H., Lipford G., Bauer S. (2002) Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol 3: 499.
  • 45
    Hemmi H., Takeuchi O., Kawai T., Kaisho T., Sato S., Sanjo H., Matsumoto M., Hoshino K., Wagner H., Takeda K., Akira S. (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408: 7405.
  • 46
    Brownlie R., Zhu J., Allan B., Mutwiri G., Babiuk L., Potter A., Griebel P. (2009) Chicken TLR21 acts as a functional homologue to mammalian TLR9 in the recognition of CpG oligodeoxynucleotides. Mol Immunol 46: 316370.
  • 47
    Yarovinsky F., Zhang D., Andersen J.F., Bannenberg G.L., Serhan C.N., Hayden M.S., Hieny S, Sutterwala F.S., Flavell R.A., Ghosh S., Sher A. (2005) TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308: 16269.
  • 48
    Desmet C.J., Ishii K.J. (2012) Nucleic acid sensing at the interface between innate and adaptive immunity in vaccination. Nat Rev Immunol 12: 47991.
  • 49
    Hibino T., Loza-Coll M., Messier C., Majeske A., Cohen A., Terwilliger D., Buckley K., Brockton V., Nair S., Berney K., Fugmann S., Anderson M., Pancer Z., Cameron R., Smith L., Rast J. (2006) The immune gene repertoire encoded in the purple sea urchin genome. Dev Biol 300: 34965.
  • 50
    Holland L., Albalat R., Azumi K., Benito-Gutiérrez E., Blow M., Bronner-Fraser M., Brunet F., Butts T., Candiani S., Dishaw L., Ferrier D., Garcia-Fernàndez J., Gibson-Brown J., Gissi C., Godzik A., Hallböök F., Hirose D., Hosomichi K., Ikuta T., Inoko H., Kasahara M., Kasamatsu J., Kawashima T., Kimura A., Kobayashi M., Kozmik Z., Kubokawa K., Laudet V., Litman G., McHardy A., Meulemans D., Nonaka M., Olinski R., Pancer Z., Pennacchio L., Pestarino M., Rast J., Rigoutsos I., Robinson-Rechavi M., Roch G., Saiga H., Sasakura Y., Satake M., Satou Y., Schubert M., Sherwood N., Shiina T., Takatori N., Tello J., Vopalensky P., Wada S., Xu A., Ye Y., Yoshida K., Yoshizaki F., Yu J., Zhang Q., Zmasek C., de Jong P., Osoegawa K., Putnam N., Rokhsar D., Satoh N., Holland P. (2008) The amphioxus genome illuminates vertebrate origins and cephalochordate biology. Genome Res 18: 110011.
  • 51
    Azumi K., De Santis R., De Tomaso A., Rigoutsos I., Yoshizaki F., Pinto M, Marino R., Shida K., Ikeda M., Arai M., Inoue Y., Shimizu T., Satoh N., Rokhsar D., Du Pasquier L., Kasahara M., Satake M., Nonaka M. (2003) Genomic analysis of immunity in a urochordate and the emergence of the vertebrate immune system: “waiting for Godot”. Immunogenetics 55: 57081.
  • 52
    Sasaki N., Ogasawara M., Sekiguchi T., Kusumoto S., Satake H. (2009) Toll-like receptors of the ascidian Ciona intestinalis: prototypes with hybrid functionalities of vertebrate Toll-like receptors. J Biol Chem 284: 2733643.
  • 53
    Seya T., Matsumoto M., Ebihara T., Oshiumi H. (2009) Functional evolution of the TICAM-1 pathway for extrinsic RNA sensing. Immunol Rev 227: 4453.
  • 54
    Honda K., Yanai H., Negishi H., Asagiri M., Sato M., Mizutani T., Shimada N., Ohba Y., Takaoka A., Yoshida N., Taniguchi T. (2005) IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434: 7727.
  • 55
    Seth R.B., Sun L., Ea C.K., Chen Z.J. (2005) Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122: 66982.
  • 56
    Kasamatsu J., Oshiumi H., Matsumoto M., Kasahara M., Seya T. (2010) Phylogenetic and expression analysis of lamprey toll-like receptors. Dev Comp Immunol 34: 85565.
  • 57
    González-Navajas J.M., Lee J, David M, Raz E. (2012) Immunomodulatory functions of type I interferons. Nat Rev Immunol 12: 12535.
  • 58
    Gately M.K., Renzetti L.M., Magram J., Stern A.S., Adorini L., Gubler U., Presky D.H. (1998) The interleukin-12/interleukin-12-receptor system: role in normal and pathologic immune responses. Annu Rev Immunol 16: 495521.
  • 59
    Kumar H., Koyama S., Ishii K.J., Kawai T., Akira S. (2008) Cutting edge: cooperation of IPS-1- and TRIF-dependent pathways in poly IC-enhanced antibody production and cytotoxic T cell responses. J Immunol 180: 6837.
  • 60
    Lugo-Villarino G., Balla K.M., Stachura D.L., Bañuelos K, Werneck M.B., Traver D. (2010) Identification of dendritic antigen-presenting cells in the zebrafish. Proc Natl Acad Sci U S A 107: 158505.
  • 61
    Bassity E., Clark T.G. (2012) Functional identification of dendritic cells in the teleost model, rainbow trout (Oncorhynchus mykiss). PLoS One 7: e33196.
  • 62
    Fujii T. (1981) Antibody-enhanced phagocytosis of lamprey polymorphonuclear leucocytes against sheep erythrocytes. Cell Tissue Res 219: 4151.